The present invention relates to pharmaceutical compositions comprising 4-quinolones or compounds derived therefrom.
A cancer is a somatic gene disorder in which genetic dysfunctions are amplified as the tumor process progresses from the state of a precancerous lesion to that of a malignant transformation, the cancer tumor becoming metastatic and often resistant to cytotoxic drugs.
Despite considerable efforts conducted in all developed countries, in particular through experimental and clinical research programs, the death rate due to the various cancers (solid tumors and hematological neoplasias) remains unacceptably high. In many countries, the cancer death rate is the second largest, just after cardiovascular diseases.
In terms of newly diagnosed cancers, the distribution between solid tumors and hematological neoplasias (bone marrow, blood, lymphatic system) shows that 9 out of 10 cancers are solid tumors. Contrary to what is observed in hematological oncology (therapeutic success in 40 to 90% of blood cell cancers), only a small number of advanced or disseminated solid tumors respond to chemotherapy treatments alone. It is partly for this reason that the overall death rate by cancer increased in the USA between 1973 and 1992.
Unfortunately, it is not sure that this tendency might be reversed solely by the appearance, alongside the established chemotherapeutic arsenal, of new antitumor drugs such as taxanes (paclitaxel and docetaxel) which interfere with the formation of microtubules (W. P. Mc Guire et al., Am. Intern. Med., 1989), topoisomerase I inhibitors derived from camptothecin (topotecan and irinotecan), vinorelbin (new alkaloid derived from periwinkle), gemcitabine (new cytotoxic antimetabolic agent), raltitrexed (thymidylate synthetase inhibitor) and miltefosine (first representative of the alkyl-lysophospholipid family) These treatments are added, either as a first line treatment or as a second line treatment, to drugs whose specific activity is now well established, for instance doxorubicin, cisplatin, vincristine, methotrexate and 5-fluorouracil.
The vast majority of the conventional chemotherapy treatments or of the treatments based on these new compounds consists in administering highly cytotoxic compounds either in monodrug therapy or in multidrug therapy. The therapeutic efficacy of these treatments is often limited by the intensity of the side effects, which makes it necessary to reduce the number of administrations and the duration of the treatments, whereas for certain solid tumors, therapeutic protocols by intensifying the dose improve the efficacy.
Another of the current difficulties in anticancer chemotherapy is due to the fact that many populations of malignant cells show considerable resistance to the established cytotoxic substances. Usually, this situation results from the existence of multidrug resistance genes or from the frequency of genetic mutations in certain types of tumor. Thus, cancer treatment requires new approaches, complementary to those currently used, and intended to combat more effectively the extension and heterogeneity of the tumor charge and the acquisition of xe2x80x9ccytotoxic multidrugxe2x80x9d resistance.
A first approach is that of preventing or treating xe2x80x9cmultidrug-resistantxe2x80x9d (MDR) cancers by using substances that inhibit or bring about the reversibility of the MDR resistance possibly associated with the expression of the glycoprotein-P membrane transporter. Such an approach is described in U.S. Pat. No. 5,726,184. Other new approaches are already showing promise. This is the case for the induction of apoptosis, the inhibition of tumor angiogenesis and metastatic processes, not to mention gene therapy or immunotherapy.
The inventors have become interested in a different approach. The desired objective was to render the tumor cell population more sensitive to the reference anticancer treatments in order to achieve a twofold benefit:
1) to increase the cytotoxic activity and thus the efficacy of cytotoxic anticancer drugs, and
2) to reduce the frequency and severity of certain side effects by means of reducing the dosage which might follow the induction of the increase in antitumor efficacy.
It is this strategy that is at the origin of the discovery of compositions capable of inducing a highly significant increase in the cytotoxic activity of tested anticancer drugs. The inventors have become interested in a particular group of novel derivatives of the 3-aryl-4-quinolone family. These compositions have the capacity either of stimulating the recruitment of clonogenic cells in the tumor, making it more sensitive to the conventional treatment with cytotoxic agents, or of inhibiting the proliferation of clonogenic cells, thus contributing toward the regression of the tumor. They have the advantage of having no intrinsic cytotoxicity, unlike, on the one hand, tyrosine kinase inhibitors of the essentially 7-chloro 3-aryl-4-quinolone family, described in WO 98/17662 and claimed in the treatment of benign or malignant tumors, and more specifically for treating psoriasis, neoplasias, in particular epithelial neoplasias, and also for treating leukemias and attacks of the immune system, and, on the other hand, 2-aryl-4-quinolone derivatives described in WO 94/02145 for their intrinsic antitumor properties.
X. Mingxia et al. (Bopuxue 1993; 927-929) have described the synthesis of 4-quinolone derivatives with estrogenic and antiosteoporotic properties. Y. L. Kanghou et al. (Zhogguo Haiyang Yaowu, 1989; 8: 2-9) have synthesized novel 4-quinolone derivatives described as antispasmodic and antiarrhythmic agents. M. Croissey et al. have proposed a synthetic process by thermal cyclization for the preparation of 2- and 4-quinolones (Heterocycle 1997, 45, 683-690), whereas Price et al. compare the infrared spectra of a series of 2- and 4-quinolone derivatives (Aust. J. Chem. 1959; 12: 589-600).
One subject of the present invention is thus the use, in the treatment of cancers with at least one antitumor agent chosen from cytotoxic agents, of a compound with activity on the proliferation of clonogenic cells in tumors, but that has no intrinsic antitumor activity (allowing a therapeutic use), which is chosen from the compounds of formulae: 
in which:
R1 is chosen from H, OH, C1-C4 alkyl groups, C2-C4 alkenyl groups, C1-C4 alkoxy groups, phenyl groups or a phenyl group substituted 1 to 3 times with groups chosen from H, OH, a group xe2x80x94OCOR7, R7 being a C1-C4 alkyl group, a group xe2x80x94Oxe2x80x94SO2xe2x80x94Rxe2x80x27, Rxe2x80x27 being a C1-C4 alkyl group or a CF3 group, and a group xe2x80x94NR16R17, R16 and R17 being chosen, independently of each other, from hydrogen, C1-C4 alkyl groups, C2-C4 alkenyl groups, phenyl(C1-C4)alkyl groups, a phenyl(C1-C4)alkyl group substituted 1 to 3 times on the alkyl group with groups chosen from H, OH and C1-C4 alkoxy, or a dimethylamino (C1-C4)alkyl group, or together forming, with the nitrogen atom, a 5- or 6-membered heterocycle optionally comprising one or more hetero atoms chosen from oxygen, nitrogen and sulfur, or a methylpiperazinyl group,
R2, R3 and R4 are chosen, independently of each other, from H, OH, a C1-C4 alkyl group, a C1-C4 alkoxy group, a group xe2x80x94OCOR7, and a group derived from a saccharide, at least one of the substituents R2, R3 or R4 being other than H, and R2 and R3 together possibly forming a methylenedioxy group,
R5 is a phenyl group or a phenyl group substituted 1 to 3 times with groups chosen from H, OH, a C1-C4 alkoxy group, a group xe2x80x94OCOxe2x80x94R7, a phenyl(C1-C4)alkoxy group, a group xe2x80x94Oxe2x80x94SO2xe2x80x94Rxe2x80x27, Rxe2x80x27 being a C1-C4 alkyl group or a CF3 group, a benzylamino group and a group derived from a saccharide,
R6 is chosen from H, a C1-C4 alkyl group, a C2-C4 alkenyl group, a group xe2x80x94COxe2x80x94R8 and a group xe2x80x94Axe2x80x94R9,
R6a is chosen from a C1-C4 alkyl group, a C2-C4 alkenyl group, a group xe2x80x94COxe2x80x94R8 and a group xe2x80x94Axe2x80x94R9,
R8 being a C1-C4 alkyl group,
A being a C1-C4 alkylene group,
R9 being chosen from 5- or 6-membered heterocyclic groups containing 1 to 4 hetero atoms chosen from oxygen, sulfur and nitrogen, CN, hydroxyl, xe2x80x94COOR10 and xe2x80x94CONR11R12 groups, a group xe2x80x94NR13R14, a group xe2x80x94COR15 and a group OSO2R16,
R10, R11, R12, R13, R14 and R15 being independently chosen from a hydrogen atom, a C1-C4 alkyl group and a phenyl (C1-C4) alkyl group,
R16 being chosen from a phenyl group and a (C1-C4)alkylphenyl group,
R4 and R6 also possibly forming together a xe2x80x94COxe2x80x94CH2xe2x80x94CH2xe2x80x94 group.
The cytotoxic agents may be used at their usual dose and, in this case, their efficacy is improved, or at lower doses given the increase in their antitumor efficacy, to reduce the severity of the side effects (e.g.: leukopenia, nausea, vomiting, etc.) that are almost always encountered.
The subject of the present invention is also a composition with activity on the proliferation of clonogenic cells in tumors by interfering with the generation of clonogenic cells, either by stimulating the proliferation and recruitment, or by inhibiting the proliferation, and which comprises an effective amount of a compound of formulae: 
in which:
R1 is chosen from H, OH, C1-C4 alkyl groups, C2-C4 alkenyl groups, C1-C4 alkoxy groups, phenyl groups or a phenyl group substituted 1 to 3 times with groups chosen from H, OH, a group xe2x80x94OCOR7, R7 being a C1-C4 alkyl group, a group xe2x80x94Oxe2x80x94SO2xe2x80x94Rxe2x80x27, Rxe2x80x27 being a C1-C4 alkyl group or a CF3 group, and a group xe2x80x94NR16R17, R16 and R17 being chosen, independently of each other, from hydrogen, C1-C4 alkyl groups, C2-C4 alkenyl groups, phenyl(C1-C4)alkyl groups, a phenyl(C1-C4)alkyl group substituted 1 to 3 times on the alkyl group with groups chosen from H, OH and C1-C4 alkoxy, or a dimethylamino (C1-C4)alkyl group, or together forming, with the nitrogen atom, a 5- or 6-membered heterocycle optionally comprising one or more hetero atoms chosen from oxygen, nitrogen and sulfur, or a methylpiperazinyl group,
R2, R3 and R4 are chosen, independently of each other, from H, OH, a C1-C4 alkyl group, a C1-C4 alkoxy group, a group xe2x80x94OCOxe2x80x94R7, and a group derived from a saccharide, R2 and R3 together possibly forming a methylenedioxy group,
R5 is a phenyl group or a phenyl group substituted 1 to 3 times with groups chosen from H, OH, a C1-C4 alkoxy group, a group xe2x80x94OCOR7, a phenyl(C1-C4)alkoxy group, a group xe2x80x94Oxe2x80x94SO2xe2x80x94Rxe2x80x27, Rxe2x80x27 being a C1-C4 alkyl group or a CF3 group, a benzylamino group and a group derived from a saccharide,
R6 is chosen from H, a C1-C4 alkyl group, a C2-C4 alkenyl group, a group xe2x80x94COxe2x80x94R8 and a group xe2x80x94Axe2x80x94R9,
R6a is chosen from a C1-C4 alkyl group, a C2-C4 alkenyl group, a group xe2x80x94COxe2x80x94R8 and a group xe2x80x94Axe2x80x94R9,
R8 being a C1-C4 alkyl group,
A being a C1-C4 alkylene group,
R9 being chosen from 5- or 6-membered heterocyclic groups containing 1 to 4 hetero atoms chosen from oxygen, sulfur and nitrogen, CN, hydroxyl, xe2x80x94COOR10 and xe2x80x94CONR11R12 groups, a group xe2x80x94NR13R14, a group xe2x80x94COR15 and a group OSO2R16,
R10, R11, R12, R13, R14 and R15 being independently chosen from a hydrogen atom, a C1-C4 alkyl group and a phenyl (C1-C4) alkyl group,
R16 being chosen from a phenyl group and a (C1-C4) alkylphenyl group,
R4 and R6 also possibly forming together a xe2x80x94COxe2x80x94CH2xe2x80x94CH2xe2x80x94 group.
The subject of the present invention is also novel compounds, namely compounds of formulae: 
in which:
R1 is chosen from H, OH, C1-C4 alkyl groups, C2-C4 alkenyl groups, C1-C4 alkoxy groups, phenyl groups or a phenyl group substituted 1 to 3 times with groups chosen from H, OH, a group xe2x80x94OCOR7, R7 being a C1-C4 alkyl group, a group xe2x80x94Oxe2x80x94SO2xe2x80x94Rxe2x80x27, Rxe2x80x27 being a C1-C4 alkyl group or a CF3 group, and a group xe2x80x94NR16R17, R16 and R17 being chosen, independently of each other, from hydrogen, C1-C4 alkyl groups, C2-C4 alkenyl groups, phenyl(C1-C4)alkyl groups, a phenyl(C1-C4)alkyl group substituted 1 to 3 times on the alkyl group with groups chosen from H, OH and C1-C4 alkoxy, or a dimethylamino (C1-C4)alkyl group, or together forming, with the nitrogen atom, a 5- or 6-membered heterocycle optionally comprising one or more hetero atoms chosen from oxygen, nitrogen and sulfur, or a methylpiperazinyl group,
R2, R3 and R4 are chosen, independently of each other, from H, OH, a C1-C4 alkyl group, a C1-C4 alkoxy group, a group xe2x80x94OCOxe2x80x94R7, and a group derived from a saccharide, R2 and R3 together possibly forming a methylenedioxy group,
R5 is a phenyl group or a phenyl group substituted 1 to 3 times with groups chosen from H, OH, a C1-C4 alkoxy group, a group xe2x80x94OCOR7, a phenyl(C1-C4)alkoxy group, a group xe2x80x94Oxe2x80x94SO2xe2x80x94Rxe2x80x27, Rxe2x80x27 being a C1-C4 alkyl group or a CF3 group, a benzylamino group and a group derived from a saccharide,
R6 is chosen from H, a C1-C4 alkyl group, a C2-C4 alkenyl group, a group xe2x80x94COxe2x80x94R8 and a group xe2x80x94Axe2x80x94R9,
R6a is chosen from a C1-C4 alkyl group, a C2-C4 alkenyl group, a group xe2x80x94COxe2x80x94R8 and a group xe2x80x94Axe2x80x94R9,
R8 being a C1-C4 alkyl group,
A being a C1-C4 alkylene group,
R9 being chosen from 5- or 6-membered heterocyclic groups containing 1 to 4 hetero atoms chosen from oxygen, sulfur and nitrogen, CN, hydroxyl, xe2x80x94COOR10 and xe2x80x94CONR11R12 groups, a group xe2x80x94NR13R14, a group xe2x80x94COR15 and a group OSO2R16,
R10, R11, R12, R13, R14 and R15 being independently chosen from a hydrogen atom, a C1-C4 alkyl group and a phenyl (C1-C4) alkyl group,
R16 being chosen from a phenyl group and a (C1-C4)alkylphenyl group,
R4 and R6 also possibly forming together a xe2x80x94COxe2x80x94CH2xe2x80x94CH2xe2x80x94 group,
with the exclusion of the compounds in which:
R1, R2, R4, R6=H, R3=OH and R5 is a phenyl, 4-methoxyphenyl, 2,4-dimethoxyphenyl or 2,5-dimethoxyphenyl group,
R1=OH or OCH3, R2=H, R3=OCH3, R4=H, R5=4-methoxyphenyl and R6=H,
R1=OCH3, R2=H, R3=OCH3, R4=H, R5=4-methoxyphenyl and R6=CH3,
R1=OH, R2=H, R3=OH, R4=H, R5=4-hydroxyphenyl and R6=CH3,
R1=H, R2=H, R3=OCH3, R4=H, R5=phenyl and R6=H,
R1=H, R2=H, R3=OCH3, R4=H, R5=phenyl and R6=CH3,
R1=H, R2=H, R3=OH, R4=OCH3, R5=phenyl and R6=H,
R1, R2, R3, R4, R6=H and R5=phenyl or 4-methoxyphenyl,
R1, R2, R3, R4, =H, R5=phenyl or 4-methoxyphenyl and R6=COCH3,
R1, R2, R3, R4, =H, R5=phenyl and R6=CH3,
R1, R2, R3, R4, R6=H and R5=4-methoxyphenyl, 2-methoxyphenyl or 4-methylphenyl.
One particular group of compounds is that consisting of the compounds of formula I or Ia in which:
R1 is chosen from H, OH, C1-C4 alkyl groups, C2-C4 alkenyl groups, C1-C4 alkoxy groups, phenyl groups or a phenyl group substituted 1 to 3 times with groups chosen from H, OH, a group xe2x80x94OCOR7, R7 being a C1-C4 alkyl group, a group xe2x80x94Oxe2x80x94SO2xe2x80x94Rxe2x80x27, Rxe2x80x27 being a C1-C4 alkyl group or a CF3 group, and a benzylamino group, R2, R3 and R4 are chosen, independently of each other, from H, OH, a C1-C4 alkyl group, a C1-C4 alkoxy group, a group xe2x80x94OCOxe2x80x94R7, and a group derived from a saccharide, R2 and R3 together possibly forming a methylenedioxy group, R5 is a phenyl group or a phenyl group substituted 1 to 3 times with groups chosen from H, OH, a C1-C4 alkoxy group, a group xe2x80x94OCOR7, a phenyl(C1-C4)alkoxy group, a group xe2x80x94Oxe2x80x94SO2-Rxe2x80x27, Rxe2x80x27 being a C1-C4 alkyl group or a CF3 group, a benzylamino group and a group derived from a saccharide,
R6 is chosen from H, a C1-C4 alkyl group, a group xe2x80x94COxe2x80x94R8 and a group xe2x80x94Axe2x80x94R9,
R6a is chosen from a C1-C4 alkyl group, a group xe2x80x94COxe2x80x94R8 and a group xe2x80x94Axe2x80x94R9,
R8 being a C1-C4 alkyl group,
A being a C1-C4 alkylene group,
R9 being chosen from 5- or 6-membered heterocyclic groups containing 1 to 4 hetero atoms chosen from oxygen, sulfur and nitrogen, a CN group, xe2x80x94COOR10 and xe2x80x94CONR11R12 groups, a group xe2x80x94NR13R14 and a group xe2x80x94COR15,
R10, R11, R12, R13, R14 and R15 being independently chosen from a hydrogen atom, a C1-C4 alkyl group and a phenyl(C1-C4) alkyl group,
R4 and R6 also possibly forming together a xe2x80x94COxe2x80x94CH2xe2x80x94CH2xe2x80x94 group.
Another particular group of compounds is that consisting of the compounds of formula I or Ia in which:
R5 is a phenyl, 4-methoxyphenyl, 2,4-dimethoxyphenyl or 2,5-dimethoxyphenyl group.
Another particular group of compounds is that consisting of the compounds of formula I or Ia in which:
R1 is chosen from C1-C4 alkyl groups, C2-C4 alkenyl groups, phenyl groups or a phenyl group substituted 1 to 3 times with groups chosen from H, OH, a group xe2x80x94OCOR7, R7 being a C1-C4 alkyl group, a group xe2x80x94Oxe2x80x94SO2xe2x80x94Rxe2x80x27, Rxe2x80x27 being a C1-C4 alkyl group or a CF3 group, and a group xe2x80x94NR16R17, R16 and R17 being chosen, independently of each other, from hydrogen, C1-C4 alkyl groups, C2-C4 alkenyl groups, phenyl(C1-C4)alkyl groups, a phenyl(C1-C4)alkyl group substituted 1 to 3 times on the alkyl group with groups chosen from H, OH and C1-C4 alkoxy, or a dimethylamino (C1-C4)alkyl group, or together forming, with the nitrogen atom, a 5- or 6-membered heterocycle optionally comprising one or more hetero atoms chosen from oxygen, nitrogen and sulfur, or a methylpiperazinyl group,
and R2, R3 and R4 are chosen from a hydrogen atom and a C1-C4 alkoxy group.
Another particular group of compounds is that consisting of the compounds of formula I or Ia in which:
R1, R2, R3 and R4 are chosen from a hydrogen atom and a C1-C4 alkoxy group.
In the preceding definitions, the expression xe2x80x9cgroup derived from a saccharidexe2x80x9d denotes a group which forms a heteroside with the rest of the molecule. On hydrolysis, these heterosides are capable of giving a compound of formula I or Ia with a hydroxyl group and a saccharide. The saccharides may especially be monosaccharides (glucose or rhamnose) or disaccharides (for example rutinose).
In the chemotherapeutic treatment of cancers with cytotoxic agents, the compounds of formulae (I) and (Ia) may be administered at the start of the chemotherapeutic treatments either once or over several days at the start of these treatments (for example from 5 to 7 days) and, depending on the chemotherapy protocol, at the start of each treatment cycle (for example for 2 to 5 days) during each cure.
The compounds of formulae (I) and (Ia) are advantageously administered by perfusion (generally for 1 to 3 hours) at doses of from 1 to 50 mg/kg/day or 40 to 2000 mg/m2/day.
In order to obtain a maximum effect on the production (inhibition or stimulation) of clonogenic cells, the compounds of formulae (I) and (Ia) must be administered such that the tissue concentrations obtained are as high as can possibly be envisaged.
For the treatment protocols in the acute phases of cures, the intravenous route is preferred, using:
ready-to-use perfusion solutions (bags, bottles, etc.) intended to be administered without modification by intravenous perfusion using a perfusion line and at the recommended flow rate;
lyophilizates to be dissolved for intravenous perfusion using pharmaceutical solutions known to those skilled in the art;
for maintenance treatments, it is also possible to envisage the oral route when the chemotherapy treatment favors the oral administration of cytostatic agents. To this end, lyophilized tablets (for oral or perlingual absorption), immediate-release or delayed-release tablets, oral solutions, suspensions, granules, gel capsules, etc. may be used.
The cytotoxic agents may be chosen from:
i) intercalating agents, in particular doxorubicin (Adriamycin), daunorubicin, epirubicin, idarubicin, zorubicin, aclarubicin, pirarubicin, acridine, mitoxanthrone, actinomycin D, eptilinium acetate;
ii) alkylating agents chosen from platinum derivatives (cisplatin, carboplatin, oxaliplatin);
iii) a compound chosen from the other groups of alkylating agents:
cyclophosphamide, ifosfamide, chlormetrine, melphalan, chlorambucil, estramustine,
busulfan, mitomycin C,
nitrosoureas: BCNU (carmustine), CCNU (lomustine), fotemustine, streptozotocin,
triazines or derivatives: procarbazine, dacarbazine,
pipobroman,
ethyleneimines: altretamine, triethylene-thio-phosphoramide,
iv) a compound chosen from the other groups of anti-metabolic agents:
antifolic agents: methotrexate, raltitrexed,
antipyrimidine agents: 5-fluorouracil (5-FU), cytarabine (Ara-C),
hydroxyurea
antipurine agents: purinethol, thioguanine, pentostatin, cladribine,
cytotoxic nucleoside synthesis inducers: gemcitabine,
v) a compound chosen from the other groups of tubulin-affinity agents,
vinca alkaloids which disrupt the mitotic spindle: vincristine, vinblastine, vindesine, navelbine,
agents which block the depolymerization of the mitotic spindle: paclitaxel, docetaxel,
agents which induce DNA cleavage by inhibition of topoisomerase II: etoposide, teniposide,
topoisomerase I inhibitors which induce DNA cleavage: topotecan, irinotecan,
vi) a DNA splitting or fragmenting agent, such as bleomycin,
vii) one of the following compounds: plicamycin, L-asparaginase, mitoguazone, dacarbazine,
viii) an anticancer progestative steroid; medroxy-progesterone, megestrol,
ix) an anticancer estrogen steroid: diethylstilbestrol; tetrasodium fosfestrol,
x) an antiestrogen agent: tamoxifen, droloxifen, raloxifen, aminoglutethimide,
xi) a steroidal antiandrogenic agent (eg cyproterone) or a non-steroidal antiandrogenic agent (flutamide, nilutamide).
In particular, the compounds of formulae (I) and (Ia) may be combined with all the major treatments with cytotoxic agents used in solid tumor polychemo-therapies, such as:
doxorubicin
alkylating agents: oxazophorines (cyclophosphamide, ifosfamide, chlorambucil, melphalan)
nitrosoureas
mitomycin C
antimetabolites such as methotrexate, 5-FU, Ara-C, capecitabine
agents which interfere with tubulin: vinca alkaloids (vincristine, vinblastine, vindesine, navelbine), taxoids (paclitaxel, docetaxel), epipo-dophyllotoxin derivatives (etoposide, teniposide)
bleomycin
topoisomerase I inhibitors: topotecan, irinotecan.
Similarly, the compounds of formulae (I) and (Ia) may be combined with the treatments with the major cytotoxic agents used in oncohematology for the treatment of blood cancers:
Hodgkin""s disease: cyclophosphamide, mechlorethamine, chlorambucil, melphalan, ifosfamide, etoposide, doxorubicin, daunorubicin;
acute leukemias: methotrexate, 6-mercaptopurine, cytarabine, vinblastine, vincristine, doxorubicin, daunorubicin, L-asparaginase;
non-Hodgkin""s malignant lymphomas: mechlorethamine, chlorambucil, cyclophosphamide, melphalan, ifosfamide, methotrexate, cytarabine, vinblastine, vincristine, etoposide, doxorubicin, daunorubicin, carmustine, lomustine, cisplatin;
chronic lymphoid leukemias: mechlorethamine, chlorambucil, cyclophosphamide, melphalan, ifosfamide.
In general, the compounds of formulae (I) and (Ia) may be prepared according to the following reaction schemes: 
A reagent of the type XR6 in which X=I, Br or Cl may be used as alkylating reagent.
In addition, it is possible to convert some or all of the alkoxy groups into hydroxyl groups according to known methods. Similarly, the hydroxyl groups may be converted into ester or sulfonate according to the known methods, the sulfonates in turn possibly being converted into alkenyl, phenyl or substituted phenyl groups and groups xe2x80x94NR16R17 according to the known methods.
Similarly, it is possible to convert, by known methods, a group xe2x80x94Axe2x80x94COOR10, in which R10 is an alkyl or phenyl-alkyl group, into a group xe2x80x94Axe2x80x94COOH and to convert a group xe2x80x94Axe2x80x94COOH into a group xe2x80x94Axe2x80x94CONR11R12.
The compounds in which R4 and R6 form a xe2x80x94COxe2x80x94CH2xe2x80x94CH2xe2x80x94 group may be obtained by cyclization of a compound in which R4=H and R6=xe2x80x94CH2xe2x80x94CH2xe2x80x94COOH.